Highly Enantioselective Reactions of Cyclohexanone and β,γ-Unsaturated α-Keto Ester: The Tuning of Chemo-selectivities by Secondary and Primary Amine Catalysts

Article abstract of DOI:10.1002/cjoc.201400431

A series of of amphiphilic imidazole based secondary and primary amine catalysts were synthesized and shown to be very effective with an acid cocatalyst for the asymmetric reaction of cyclohexanone to β,γ-unsaturated α-keto ester. Interestingly, primary a

Full text of DOI:10.1002/cjoc.201400431

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DOI: 10.1002/cjoc.201400431
Highly Enantioselective Reactions of Cyclohexanone and
β,γ-Unsaturated α-Keto Ester: The Tuning of Chemo-
selectivities by Secondary and Primary Amine Catalysts†
Jianwei Wei,a,b Wengang Guo,a Xin Zhou,a Xin Du,b Yan Liu,*,a and Can Li*,a
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences,
Dalian, Liaoning 116023, China
b Department of Chemistry, Dalian University of Technology, Dalian, Liaoning 116024, China
A series of of amphiphilic imidazole based secondary and primary amine catalysts were synthesized and shown
to be very effective with an acid cocatalyst for the asymmetric reaction of cyclohexanone to β,γ-unsaturated α-keto
ester. Interestingly, primary and secondary amine catalysts show different regio-selectivities in this reaction. Under
the catalysis of secondary amine 1, excellent enantioselectivities were observed for the products from direct 3＋3
reactions of cyclohexanone with β,γ-unsaturated α-keto esters using water as the solvent. Moreover, the same reac-
tants catalyzed by the primary amines 2 lead to the aldol reactions, affording the corresponding products with high
diastereoselectivities and up to 97% ee. Theoretical studies on the transition states by using a model in gas phase
revealed that steric effect plays an important role on different chemo-selective induction between the secondary
amine 1 and primary amine 2.
Keywords emulsion catalysis, asymmetric catalysis, organocatalysis
Introduction
2007, Barbas reported a syn-selective aldol reaction
between hydroxyketones and aromatic aldehydes cata-
lyzed by the primary amine catalyst. Differed from the
(E)-enamine in the C－C bond forming transition state
formed by secondary amine, (Z)-enamine was induced
by the hydrogen bonding interaction between the NH
group in the primary amine and the OH group of hy-
droxyacetone, which leads to the formation of
syn-aldol products.[3] Following the similar active model,
several asymmetric 1,2-addition could realize fully di-
astereoselective control with primary amine and secon-
dary amine catalysts[4] (Scheme 1.1).
Recently, our group developed a new amphiphilic
proline-derived imidazole organocatalysts and has
shown its effectiveness in the cascade reaction of
α-ketoacids with aldehydes using water as the solvent.[5]
The success on this type of catalyst motivated us to de-
velop new amphiphilic imidazole-based organocata-
lysts.[6] Herein, we prepared a new class of imidazole
derived seconary and primary catalysts from natural
amino acid and tested the performance of them in the
asymmetric reaction of cyclohexanone to β,γ-unsatu-
rated α-keto ester. To our surprise, primary and secon-
dary amine show the different chemo-selectivities in this
reaction (Scheme 1.2). Secondary amine catalysts 1 can
Formation of enamine from the condensation of
chiral amines catalysts with aldehydes or ketones can be
used as an effective strategy for the acceleration of a
wide variety of catalytic asymmetric reactions.[1] Since
the proline was discovered to be an available catalyst in
the intermolecular aldol reactions via the enamine
mechanism by List and Barbas in 2000,[1b] various
amines derived from natural amino acids and other
chiral amines have been demonstrated to be effective
enamine catalysts in a wide range of enantioselective
organic reactions. Generally, secondary and primary
amines represent two categories of chiral amine cata-
lysts. Seconary amines with pyrrolidine core are re-
garded as the extremely powerful catalysts and domi-
nated the field of enamine catalysis in early years. Re-
cently, several primary amines derived from natural
amino acids were found to be the effective enamine
catalysts as the complementary of secondary amine
catalysts.[2] Moreover, in contrast with the secondary
amines, primary amine catalysts show distinct advan-
tages in virtue of the presence of the hydrogen on the
nitrogen atom, which can facilitate the formation of an
active catalytic intermediate to control the enamine
structure and selectivity of the reaction. For example, in
*
E-mail: yanliu503@dicp.ac.cn; canli@dicp.ac.cn; Tel.: 0086-0411-84379307; Fax: 0086-0411-84694447
Received June 30, 2014; accepted September 3, 2014; published online September 29, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400431 or from the author.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 985—990
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Wei et al.
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focused on the reactions of cyclohexanone with β,γ-un-
saturated α-keto ester[7] which have been reported by
three groups. These reactions can produce chiral [3,3,1]
bicycle,[8] chiral alcohols[9] with two adjacent chiral
centers and chiral fused dipyrans[10] via 3＋3 annulation,
aldol reaction and Hetero-Diels-Alder reaction sepa-
rately. We began our investigation on the asymmetric
reaction of cyclohexanone (3a) to β,γ-unsaturated α-keto
ester (4a) in water[11] by using a 20 mol% catalyst load-
ing at room temperature. Firstly, secondary amine cata-
lysts 1a－1e were screened and the results were listed in
Entries 1－5 of Table 1. It was found that all the secon-
dary amine catalysts 1a－1e could promote the reaction
with an additive of 4-methoxybenzoic acid (20 mol%),
affording 2-hydroxy-9-oxo-bicyclo[3,3,1]nonane (5a)
via 3＋3 tandem annulation with 80%－90% ee. Judg-
ing from its appearance, the reaction mixture displayed
stable emulsion[12] when catalysts 1a－1e were added.
Comparably, the emulsion could not form on adding
non-carbon-chained catalyst 1a or short carbon-chained
catalyst 1b. Accordingly, we found that reactivities were
increasing as the emulsion of the reaction system be-
came more stable. When 18 or 22-carbon chain com-
afford highly optically active 2-hydroxy-9-oxo-bicyclo
[3.3.1] nonane derivatives with four stereo centers via
formal 3＋3 annulation reaction using water as solvent.
The same reactants catalyzed by primary amines lead to
the aldol reactions, affording the corresponding products
bearing two adjacent chiral centers with high diastereo-
selectivities and up to 97% ee. Moreover, theoretical
studies on the possible transition states of different
catalyst in the control of regio-selectivities of the reac-
tion of cyclohexanone to β,γ-unsaturated α-keto ester
are also discussed.
Results and Discussion
The synthesis of catalysts 1 and 2 was quite simple.
The key intermediates, N-Cbz protected mercapto imi-
dazoles were readily prepared by the condensation of
mercapto imidazole with N-Cbz-protected amino bro-
mide (see Supporting Information). A series of catalysts
1 and 2 were finally obtained after the grafting of hy-
drophobic alkyl chains with different lengths and the
deprotection of Cbz group in good yields
To explore the catalytic performance of 1 and 2, we
Scheme 1 Different induced selectivities of the primary amine and secondary amine catalysts
1.1 The reported results: The diastereo-selective control with primary amine and secondary catalysts
O
OH
Ar
*
*
O
O
OH
Ar
N
O
NH2
H
R2
R2
+
R2
R1
Ar
H
R1
R1 = OH, OAlkyl-, Alkyl
R2 = H, CH2OH, CH2OAlkyl, Alkyl-
R1
anti-products
syn-products
*
*
O
O
NHP
Ar
OR1
NHP
Ar
OR1
O
N
NP
NH2
H
R2
R2
R2
+
Ar
H
OR1
R1 = H or Alkyl
R2 = CH2OAlkyl, Alkyl-
anti-products
syn-products
1.2 This work: The chemo-selective control with primary amine and secondary catalysts
n
N
S
N
Catalyst
(10 or 20 mol%)
O
CO2R
O
HO CO2R
O
=
=
O
HO
H
Ar
H
N
NH2
H
O
Ar
R'
+
10 mol% additive
H2O
R
20 mol% additive
CH2Cl2
O
－
92% 97% ee
88% 93% ee
－
986
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Chin. J. Chem. 2014, 32, 985—990

Highly Enantioselective Reactions of Cyclohexanone and β,γ-Unsaturated α-Keto Ester
system. To our surprise, the different regio-selectivity
R
R
was achieved which gave the aldol product 6a with the
complete conversion and 47% ee in 12 h. To further
improve enantioselectivity, solvents, additives and cata-
lysts have been screened and the results were summa-
rized in Entries 10－15 of Table 1. Finally we found
that using CH2Cl2 as the solvent could increase the en-
antioselectivity to 95% with the additive of 4-nitrophe-
nol catalyzed by 2d at the price of reactivity (Entry 13,
Table 1).
N
N
N
S
S
N
N
NH2
H
2
1
2a: R = H
1a: R = H
2b: R = n-C4H9
2c: R = n-C12H25
2d: R = n-C16H37
1b: R = n-C4H9
1c: R = n-C12H25
1d: R = n-C18H37
1e: R = n-C22H45
Figure 1 Amphiphilic amino acids-derived mercapto imidazole
Thus, two optimal conditions were set up for 3＋3
reaction and aldol reaction separately. Various β,γ-un-
saturated α-keto esters were examined to evaluate the
reaction scope. 1d-Catalyzed asymmetric reactions of
cyclohexanone (3a) with different β,γ-unsaturated
α-keto ester (4) afforded the corresponding 3＋3 prod-
ucts with excellent ee values (88%－93%, Table 2, En-
tries 1－11). Substituted group situated at different po-
sitions on the phenyl ring and different ester group have
little impact on the enantioselectivity of the reaction.
Moreover, compared with the reported procedure (neat
condition, 20 mol% catalyst loading and 24－168 h re-
action time), emulsion catalytic system composed of 2d
and using water as solvent showed higher reactivity and
efficiency. For the aldol 4-nitrophenol was proved to be
effective. Under the optimized conditions, a variety of
organocatalysts.
pound 1d or 1e was selected to be catalyst, it can
achieve over 80% conversion and 90% ee (Entries 4, 5,
Table 1). By using benzoic acid instead of 4-methoxy-
benzoic acid, almost the same result was achieved (En-
try 6, Table 1). By prolonging the reaction time to 12 h,
1d afforded a conversion of over 95% and enantioselec-
tivity of 91% (Entry 7, Table 1). To prove the high effi-
ciency of emulsion system, the model reaction was car-
ried out with a reduced catalyst loading (5 mol%),
thereby affording 5a with a 90% conversion with the
enantioselectivity as high as 91% by increasing the re-
action time to 72 h (Entry 8). Amphiphilic primary
catalyst 2d was then investigated in the same reaction
Table 1 The catalytic asymmetric reactions of 3a and 4aa
CO2Me
O
HO CO2Me
O
O
HO
H
Ph
H
O
Catalyst (20 mol%)
Ph
OMe
Ph
+
Additive (20 mol%)
H2O
O
aldol product
6a
3a
4a
[3+3] product
5a
Entry
Cat.
Additive
Time/h
Conv.b/%
Prod.
eec/%
1
2
1a
1b
1c
1d
1e
1d
1d
1d
2d
2a
2b
2c
2d
2d
2d
4-MeO-BA
4-MeO-BA
4-MeO-BA
4-MeO-BA
4-MeO-BA
BA
6
6
19
45
5a
5a
5a
5a
5a
5a
5a
5a
6a
6a
6a
6a
6a
6a
6a
80
90
90
90
90
91
91
91
47
94
91
93
95
89
89
3
6
78
4
6
84
5
6
87
6
6
84
7
8d
BA
12
72
12
36
36
36
36
36
36
＞95
90
BA
9
BA
＞95
＞95
＞95
＞95
＞95
＞95
＞95
10e
11e
12e
13e
14e
15e
4-Nitro-P
4-Nitro-P
4-Nitro-P
4-Nitro-P
BA
4-MeO-BA
a Unless otherwise noted, the reaction was conducted in solvent H2O (0.5 mL for catalyst 1, 0.05 mL for catalyst 2) by using 3a (124 μL,
1.2 mmol), 4a (38 mg, 0.2 mmol), and catalyst 1 (0.04 mmol) in the presence of 20 mol% additive at room temperature; b determined by
crude 1H NMR; c determined by chiral HPLC; d catalyst loading: 5 mol%; e CH2Cl2 as the solvent; BA: benzoic acid; P: phenol.
Chin. J. Chem. 2014, 32, 985—990
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Wei et al.
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β,γ-unsaturated α-keto esters (4) were reacted with
cyclohexanone (3a) to afford the corresponding aldol
products with high diastereoselectivities and excellent
enantioselectivities (Table 3, Entries 1－14).
Continued
Entry
Ar
R
t/h
Yieldb/%
drc eed/%
11
14
p-CH3C6H4
Me 48
Me 96
60
60
5∶1 97
6∶1 92
2-Thienyl
a
Table 2 Substrates scope of the [3＋3] annulation reactiona
Unless otherwise specified, the reaction was conducted in
CH2Cl2 (0.5 mL) by using 3a (62 μL, 0.6 mmol), 4 (0.1 mmol),
and catalyst 2d (0.02 mmol) in the presence of 20 mol% of
CO2R
O
HO
H
Ar
H
O
b
O
1d (20 mol%)
4-nitrophenol at room temperature; isolated yield of the major
OR
c
1
d
+
Ar
isomers; determined by crude H NMR; determined by chiral
HPLC.
C6H5COOH (20 mol%)
H2O
O
4
3a
5
A question is posed regarding why the secondary
amine and primary amine catalyst induce the different
chemoselectivities. To further understand the factors of
controlling the chemoselectivity, two kinds of enamine
models catalyzed by secondary amine and primary
amine, which represent the intermediates of 3＋3 reac-
tion and aldol reaction separately, were studied by
theoretical calculations with the Gaussian 09 program.
Geometries were fully optimized and characterized by
frequency analysis method by using hybrid density
functional theory (B3LYP) and the 6-31G(d) basis set.
As shown in Figure 2, using the primary amine 2 as the
catalyst, the intermediate enamine-I was predicted to be
a little more favorable than the enamine-II with a
slightly lower enthalpy of about 0.48 kcal/mol in the gas
phase for the best two different intermediates
(enamine-1 and enamine-2), which means that the aldol
reaction has an advantage on the competition with
1,4-addition. On the other hand, perhaps owing to the
steric affection between secondary amine and substrates,
the intermediate enamine-IV, which represents the for-
mation of the 1,4-addtion adduct was predicted to be a
little more favorable than the enamine-III with lower en-
thalpy of about 0.66 kcal/mol under the catalysis of
secondary amine 1.
Entry
Ar
C6H5
R
Time/h
12
Yieldb/%
80
eec/%
91
1
2
Me
C6H5
C6H5
C6H5
Et
12
80
90
3
Bn
t-Bu
12
60
91
4
12
80
93
5
m-MeC6H4 t-Bu
p-MeC6H4 t-Bu
p-MeOC6H4 t-Bu
12
99
89
6
12
99
92
7
24
67
88
8
p-FC6H4
t-Bu
t-Bu
12
99
90
9
m-BrC6H4
12
90
91
10
11
p-CF3C6H4 t-Bu
p-ClC6H4 t-Bu
12
77
90
12
75
92
a Unless otherwise noted, the reaction was conducted in solvent
H2O (0.5 mL) by using 3 (1.2 mmol), 4 (0.2 mmol), and catalyst
1d (0.04 mmol) in the presence of 20 mol% of C6H5COOH at
room temperature; b isolated yield; c determined by chiral HPLC.
Table 3 Substrates scope of the cross-aldol reactiona
O
Conclusions
HO CO2R
3a
+
O
2d (20 mol%)
Ar
In conclusion, a series of amphiphilic imidazole de-
rived seconary and primary amines from natural amino
acids have been synthesized and applied in the reaction
of cyclohexanone to β,γ-unsaturated α-keto ester. The
secondary amine catalysts 1 were demonstrated to be
efficient catalysts for the 3＋3 reaction. In the presence
of 5－20 mol% of the catalyst, excellent enantio-
selectivities ranging from 88% to 92% ee and high
chemo-selectivities were observed for the products from
direct 3＋3 reactions of cyclohexanone with a broad
scope of β,γ-unsaturated α-keto esters using water as the
solvent. Moreover, the same reactants catalyzed by the
primary amines 2 lead to the aldol reactions, affording
the corresponding products bearing two adjacent chiral
centers with high diastereoselectivities and up to 97% ee.
Theoretical studies on the transition states by using a
model in gas phase revealed that steric effect plays an
important role on the different chemo-selective induc-
4-Nitrophenol (20 mol%)
CH2Cl2
O
OR
Ar
6
O
4
Entry
Ar
R
t/h
Yieldb/%
drc eed/%
1
2
Ph
Ph
Ph
Ph
Me 48
Et 72
i-pr 72
Bn 72
Me 48
Me 48
Me 48
Me 48
Me 48
Me 48
60
62
58
60
75
76
74
75
77
78
5∶1 95
5∶1 97
4∶1 97
6∶1 93
5∶1 94
5∶1 96
6∶1 96
5∶1 97
5∶1 95
5∶1 94
3
4
5
p-FC6H4
6
p-ClC6H4
p-BrC6H4
o-ClC6H4
m-ClC6H4
p-CF3C6H4
7
8
9
10
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Chin. J. Chem. 2014, 32, 985—990

Highly Enantioselective Reactions of Cyclohexanone and β,γ-Unsaturated α-Keto Ester
Figure 2 Intermediates and different reaction pathways.
tion between the secondary amine 1 and primary amine
2.
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Chin. J. Chem. 2014, 32, 985—990
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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989

Wei et al.
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990
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Chin. J. Chem. 2014, 32, 985—990